Characterization of SMARCAL1:its expression/interactors

描述（由申请方提供）：Schimke免疫性骨发育不良（SIOD）是一种常染色体隐性脊柱-骨骺发育不良，其特征为1）不成比例的身材矮小伴色素沉着斑和畸形面部特征，2）蛋白尿伴进行性肾衰竭，3）淋巴细胞减少伴细胞免疫缺陷。此外，SIOD患者甲状腺功能障碍、骨髓发育不良、眼部异常和脑缺血的发生率较高。进行性肾功能衰竭、免疫缺陷、骨髓发育不全和脑缺血是导致高发病率和死亡率的重要原因。透析和肾移植是治疗进展性肾功能衰竭的唯一有效方法，骨髓移植是治疗血细胞减少的唯一有效方法。对于生长障碍和脑缺血，目前尚无有效的治疗方法。在过去的5年里，我收集了26个家庭的SIOD患者的DNA样本和临床信息。利用四个家庭中的父母是近亲，我最近完成了全基因组筛选和映射SIOD染色体2 q34-q35。随后，通过候选基因的方法，我已经确定了26个无关的SIOD患者的SMARCAL 1基因的隐性突变。SMARCAL 1蛋白是SNF 2蛋白，在单链DNA存在下具有ATP酶活性，但其功能尚不明确。该提案的目标是鉴定与SMARCAL 1相互作用的蛋白质，并定义保守氨基酸的功能;这项研究是我的K 08的一个很好的补充，该研究专注于利用果蝇遗传学的力量来定义SMARCAL 1运作的途径。这种结合遗传和生物化学方法来描述SMARCAL 1的功能将增加我们对SMARCAL 1的生物学及其对生物体发育的调节的理解，并提供对该基因突变引起SIOD的机制的深入了解。

DESCRIPTION (provided by applicant):Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive spondylo-epiphyseal dysplasia characterized by 1) disproportionate short stature with hyperpigmented macules and dysmorphic facial features, 2) proteinuria with progressive renal failure and 3) lymphopenia with defective cellular immunity. In addition, patients with SIOD have a high incidence of thyroid dysfunction, bone marrow hypoplasia, ocular abnormalities, and cerebral ischemia. The progressive renal failure, immunodeficiency, bone marrow hypoplasia and cerebral ischemia cause significant morbidity and mortality. Dialysis and renal transplantation are the only effective treatments for the progressive renal failure and bone marrow transplantation for the blood cytopenia. There are no effective therapies for the growth failure and cerebral ischemia. Nearly all patients die within the first 15 years of life.Over the past 5 years, I have collected DNA samples and clinical information on SIOD patients from 26 families. Using four families in which the parents were consanguineous, I have recently completed a genome-wide screen and mapped SIOD to chromosome 2q34-q35. Subsequently by a candidate gene approach, I have identified recessive mutations in the SMARCAL1 gene in 26 unrelated SIOD patients. The SMARCAL1 protein, which is an SNF2 protein, has ATPase activity in the presence of single stranded DNA, but its function is otherwise undefined. The goal of this proposal is to identify proteins interacting with SMARCAL1 and to define the function of conserved amino acids; this research is an excellent adjunct to my K08 which is focused on using the power of Drosophila melanogaster genetics to define the pathways within which SMARCAL1 operates. This combined genetic and biochemical approach to delineating the function of SMARCAL1 will increase our understanding of the biology of SMARCAL1 and it regulation of organism development as well as provide insight into the mechanism by which mutations in this gene can give rise to SIOD.